Post on 15-Jan-2016
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Goals
• Understand the differences between Hodgkin Lymphoma and non-Hodgkin Lymphoma– Clinically and biologically
• Understand the differences between aggressive NHL and indolent NHL– Clinically and biologically
Definition of Lymphoma
• Heterogeneous group of lymphoproliferative malignancies– Results from clonal expansion of tumor cells derived from B, T, or
NK cells– 85%-90% in the US are derived from B cells
• Variable clinical presentations– Range from asymptomatic pick up on routine blood work to
painless adenopathy to an emergent medical problem• Pain, failure to thrive, organ failure
• Characterized by variable natural histories and therapeutic responses
C
0
20
40
60
80
100
120
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85
NHL
Hodgkin’s
~56,390 NHL cases/y
~7,350 HD cases/y
Age at Diagnosis for Hodgkin’s andNon-Hodgkin’s Lymphoma
Data for diagnoses from 1997 to 2001.At: http://seer.cancer.gov. Accessed March 23, 2005.
Age at diagnosis (y)
Ca
ses
/10
0,0
00
Adapted from Greenlee et al. CA Cancer J Clin. 2001;51:15. Adapted from Jemal et al. CA Cancer J Clin. 2005;55:10.
United States
0
15,000
30,000
45,000
60,000
1980 1985 1990 1995 2000 2005
Est
imat
ed a
nn
ual
in
cid
ence
Year
~4% compound annual increase in incidence
Non-Hodgkin’s Lymphoma:Epidemiology
Hodgkin’s Disease
Hodgkin Biology
• RS is a “crippled” germinal center B cell– does not have normal B cell surface antigens– micromanipulation of single RS followed by PCR demonstrates
clonally rearranged, but non functional immunoglobulin genes• somatic mutations result in stop codon (no sIg)
• no apoptotic death malignant transformation
– unclear how this occurs; ? EBV– unclear how cells end up with RS phenotype
Hodgkin’s Disease
• Clinical features– Often seen in young adults– Wide variety of presentations
• B symptoms (fevers, night sweats, wt loss)• Pruritis• Cough/SOB• Pain• Painless adenopathy
Hodgkin’s Disease
• Approach to the Patient– staging evaluation
• H & P• CBC, diff, plts• ESR, LDH, albumin, LFT’s, Cr• CT scans chest/abd/pelvis• bone marrow evaluation• PET scan in selected cases
Ann Arbor Staging System for Hodgkin's Disease and Non-Hodgkin's Lymphoma
Stage I Stage II Stage III Stage IV
Reprinted with permission. Adapted from Skarin. Dana-Farber Cancer Institute Atlas
of Diagnostic Oncology. 1991.
Hodgkin’s Disease
• Typical staging results– Most often disease is localized to above the diaphragm– Common to have extensive mediastinal disease
• Tends to spread to contiguous nodal groups– Unlike NHL
Approach to the Patient
• Hodgkin’s Disease– approach dictated mainly by where the disease is
located rather (results of staging) than the exact histologic subtype
• NHL– approach is often dictated more by the histologic
subtype than the results of staging
Hodgkin Lymphoma: Treatment of limited stage disease
Hodgkin Lymphoma: Prognostic Factors
Hodgkins Disease Summary
• B cell lymphoma- several histologic subtypes
- Generally does not affect the approach to the patient
– Reed-Sternberg Cells
• Tends to occur in young adults• Mediastinal disease common• Spreads to contiguous nodes• Common to have a “localized” presentation• Highly curable with current treatments
Non-Hodgkin’s Lymphoma
• 30ish histologic subtypes– B cell (85%), T cell, NK cell– Histologic subtype dictates the approach to the patient
• Median age at diagnosis 60• Often widespread disease at diagnosis• Wide variation in outcome
– Some cases rapidly fatal– Some cases readily curable– Some cases incurable but patient can live for many years with
good quality of life
WHO Classification:B-Cell Malignancies
Harris NL et al. J Clin Oncol. 1999;17:3835-3849.
Precursor B-cell neoplasm
• Precursor B-lymphoblastic leukemia/lymphoma
Mature (peripheral) B-cell neoplasms
• B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma
• B-cell prolymphocytic leukemia
• Lymphoplasmacytic lymphoma
• Splenic marginal-zone B-cell lymphoma
• Nodal marginal-zone lymphoma
• Extranodal marginal-zone B-cell lymphoma, mucosa-associated lymphoid tissue (MALT) type
• Hairy cell leukemia
• Plasma-cell myeloma/plasmacytoma
• Follicular lymphoma
• Mantle-cell lymphoma
• Diffuse large B-cell lymphoma (DLBCL)
• Burkitt's lymphoma/Burkitt's cell leukemia
• Blastic NK-cell leukemia
WHO Classification:T-Cell MalignanciesPrecursor T-cell neoplasm• Precursor T-lymphoblastic leukemia/lymphoma
Mature (peripheral) T-cell neoplasms• T-cell prolymphocytic leukemia
• T-cell granular lymphocytic leukemia
• Aggressive NK-cell leukemia
• Adult T-cell lymphoma/leukemia (HTLV1+)
• Extranodal NK/T-cell lymphoma, nasal type
• Enteropathy-type T-cell lymphoma
• Hepatosplenic gamma-delta T-cell lymphoma
• Subcutaneous panniculitis-like T-cell lymphoma
• Mycosis fungoides/Sézary syndrome
• Primary cutaneous anaplastic large cell lymphoma, T/null cell
• Peripheral T-cell lymphoma, unspecified
• Angioimmunoblastic T-cell lymphoma
• Primary systemic anaplastic large cell lymphoma, T/null cell
• Blastic NK lymphoma
Harris NL et al. J Clin Oncol. 1999;17:3835-3849.
B-Cell Development
MUM1
HLA-DR CD34
Stem cell
Pre-pre–B cell
Pre–B cell
Immature B cell
Mature B cell
HLA-DR CD19
HLA-DR CD19
HLA-DR
CD19
CD20
CD21
CD22CD79a
s-IgM
CD20
CD10
CD79a
s-IgM & IgD
CD19CD20
CD21
CD22
HLA-DR
s-IgM/G/A
s-IgM/G/A
CD79a
CD19
CD20
CD21
CD22
HLA-DR
CD10
CD19
CD20
CD138±
CD22
HLA-DR
CD79a
CD79a CD138
PCA-1
Follicle-center B cell
Immunoblast
Plasma cell
Precursor cells
Virgin (naïve) B cells
Germinal-center and post–germinal-center B cells
MUM1
TdT
TdTc-CD22c-CD79a
TdTc-CD22c-CD79a
c-
bcl6
c-Ig
c-Ig
Antigen Expression in B-Cell Lineage
Pre-B Early B Mature B Plasmacytoid B
Type of B cell lymphoma is a function of:
1) Where the cell was in development/maturation when it went “bad”
2) What molecular derangement occurred
PlasmaActivated BStem cell
Burkitts, FL, DLBCL WM MMMCL, CLLALL
Germinal center
Jaffe. In: Non-Hodgkin’s Lymphoma. 1997:84.
Models of Chromosomal Translocations in NHL
REG = regulatory sequence.Harris NL et al. Hematology (Am Soc Hematol Educ Program). 2001:194-220.
Proto-oncogene
Proto-oncogene
TRANSCRIPTIONALDEREGULATION
FUSIONPROTEIN
TRANSLOCATION TRANSLOCATION
REG
REG REG
REG
REG REGCODING CODING
COD
CODING CODING
CODING ING
Chromosomal Translocations Commonly Associated With Activation in B-Cell Malignancies
National Comprehensive Cancer Network. Practice Guidelines in Oncology. v.1.2005.
Oncogene Protein Translocation Disease
bcl-1 Cyclin D1 t(11;14) MCL
bcl-2BCL2
(antiapoptosis)t(14;18) FL
myc Transcription factor t(8;14) Burkitt’s NHL
bcl-6Zinc-finger
transcription factort(3;14)
DLBCL (some follicular NHL)
Lymphoma Biology
• Aggressive NHL– short natural history (patients die within months if
untreated)– disease of rapid cellular proliferation– Potentially curable with chemotherapy
• Indolent NHL– long natural history (patients can live for many years
untreated)– disease of slow cellular accumulation– Generally incurable with chemotherapy
NHL: Presentation and Staging
• Aggressive NHL– Patients likely to present with symptoms
• Indolent NHL– Patients likely to present with painless adenopathy
• Initial workup similar to Hodgkin Lymphoma
NHL: Approach to the Patient
• Approach dictated mainly by histology– reliable hematopathology crucial
• Aggressive NHL– Cure is often the goal
• Indolent NHL– Cure is rarely the goal– Control is the goal
Most Common NHLs
Category Frequency (%)
Diffuse large B-cell 31
Follicular 22
Marginal-zone B-cell, MALT 8
Peripheral T-cell 7
Small B-lymphocytic/CLL 7
Mantle-cell lymphoma 6
Primary mediastinal large B-cell 2
Anaplastic large T/null cell 2
High-grade B-cell, Burkitt-like 2
Marginal-zone B-cell, nodal 2
Precursor T-lymphoblastic lymphoma 2
Armitage JO, Weisenburger DD. J Clin Oncol. 1998;16:2780-2795.
Follicular Lymphoma
Approach to Indolent NHL
• Indolent NHL: guiding treatment principle• immediate treatment does not prolong overall survival for many
patients
– When to treat?• constitutional symptoms• compromise of a vital organ by compression or infiltration, particularly
the bone marrow• bulky adenopathy• rapid progression• evidence of transformation
• Will often begin with relatively non-toxic treatments and escalate the intensity of the therapy
Diffuse Large B Cell Lymphoma
Approach to Aggressive NHL
• Patients have the potential to be cured– Administer most effective therapy (no matter how
harsh) at diagnosis– If not cured, patients typically die within a few years of
diagnosis
International Prognostic Index for Age-Adjusted
Factor Adverse
PS ≥2
LDH >Normal
Stage III-IV
Risk Group
Number of Factors Present
5-year DFSAge≤60
(%)
5-year OS Age≤60
(%)
Low 0 86 83
Low-Intermediate 1 66 69
High-Intermediate 2 53 46
High 3 58 32
The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med. 1993;329:987-994.
DLBCL: Subtypes Revealed by Expression Array
Pro
bab
ilit
y
Overall survival (years)
0 2 4 6 8 10
Germinal-centerB-cell–like
ActivatedB-cell–like
P = 7.9 E-6
1.0
0.8
0.6
0.4
0.2
0.0
Alizadeh AA et al. Nature. 2000;403:503-511.
Single histology with multiple molecular
subtypes
…with different outcomes
Summary
• NHL incidence increasing • Hodgkin incidence stable or decreasing• Hodgkin Lymphoma
– Characterized by the Reed-Sternberg Cells– Stage more important that histologic subtype– Often limited stage (stage I or II)– Spreads to contiguous nodes– Often affects younger patients– Very responsive to therapy– Cure rate quite high
Summary
• NHL cure rate mediocre– Many histologic subtypes
• Often more important that the stage
– indolent vs. aggressive• Function of underlying biology
– indolent: • Often asymptomatic• Treatment: Less is more
– aggressive: • Often symptomatic• require aggressive treatment ASAP to achieve cure